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Pharmacokinetics of inhalational agents

Created: 21/4/2006
a. Define and explain the concept of partition coefficients, boiling point and saturated vapour pressure.

Partition coefficient

The ratio of the amount of substance present in one phase compared with another, the two phases being of equal volume and in equilibrium at a specified temperature.
The partition coefficient is a measure of the relative solubility of a compound in two specified phases (gas, liquid or solid). For example, the blood-gas partition coefficient of N2O at 37°C is 0.47. That is, at equilibrium, the concentration of N2O in blood is 0.47 times that of N2O in a gas in contact with the blood.
This is a useful measure of how quickly one phase can become saturated and of the quantity of compound which will be taken up by one phase over time. It is applied to volatile anaesthetic agents and gases in partition with blood, tissues and the materials in the anaesthetic circuit. It is also applied in other solution equilibria such as in chromatography.

Boiling point

The temperature at which a compound changes entirely from liquid to gas at standard pressure (101.325 kPa).
At boiling point the mean kinetic energy of individual molecules in a liquid is sufficient to overcome the attractive forces between them, allowing them to separate into a gas.

Saturated vapour pressure

The pressure at which (at a specified temperature) a compound begins to condense from gas into liquid.

At any temperature below the critical temperature, a gas can be liquefied by compression. As the saturated vapour pressure is reached, the volume of the gas and liquid can be reduced without further increase in pressure until all the gas is condensed to liquid.
Any sealed container of liquid contains in the space above the liquid, gas at saturated vapour pressure, this pressure being dependent on temperature. In the case of N2O at 20°C, the SVP is 5.25 MPa, in the case of water at 37°C, it is 47 mmHg.

b. Define MAC, MACawake, MAC-hr and MAC-BAR and outline their value and limitations of each as well as describe the factors affecting them and how they are measured.


Minimum Alveolar Concentration of an agent at equilibrium at 1 atmosphere pressure in oxygen needed to suppress purposeful movement in response to a standard surgical stimulus in 50% of subjects.

MAC is a useful measure of the relative potency of inhaled anaesthetic agents and a guide to the concentration required to eliminate awareness. It is also used to standardize comparable doses of inhaled agents for research purposes.
Its limitations are that it is a population mean which is not representative of the response of an individual to an inhaled agent and it requires measurement of alveolar gas which can only be approximated by clinical monitors. The sedative response to 1 MAC is standardized, but EEG findings at higher MAC levels differ between agents; it is an oversimplification of the response to inhaled agents.

MAC Increased
Infants, hyperthermia, thyrotoxicosis, alcoholism, central stimulants

MAC Decreased
Old age, pregnancy, hypothermia, MAP < 40 mmHg, PaCO2 > 95 mmHg, PO2 < 38 mmHg, sedative or anaesthetic drugs

MAC is measured in humans with a skin incision in the forearm and in animals using other standards. It is approximated in individual patients by analysis of endexpiratory gas for concentrations of N2O and volatile agents.

The MAC needed to abolish eye opening on command in 50% of subjects. 
Approximately equal to 0.5 MAC
Subject to the same limitations and influencing variables as MAC. It is used as a means of comparing the sedative effect of inhaled agents.

The integral of MAC by time for exposure of an individual patient to an inhaled agent.
Exposure to 1.5 MAC of an agent for 30 minutes represents 0.75 MAC-hr exposure. This is used as a comparative measure of exposure to an inhaled agent in calculation of adverse effects of inhaled agents and for setting dose-limits.
It is easily calculated but if used in setting safe doses, does not take into account differences in metabolism and effects which may occur at different concentrations, nor the effects of other factors in an agent's safety such as the level of fresh gas flow and flushing of metabolites from the circuit.

The MAC needed to abolish the sympathetic response to a surgical stimulus in 50% of patients. Approximately equal to 1.5 MAC
Sympathetic response is measured as changes in heart rate or blood pressure or plasma noradrenaline levels.

c. Explain and apply the concepts of the concentration effect and the second gas effect.

d. Explain how uptake is affected by factors such as alveolar ventilation, cardiac output, shock states and ventilation-perfusion inequalities.

e. Explain the significance of the distribution of cardiac output and tissue partition coefficient on uptake and distribution of volatile agents.

f. Explain how patients recover from volatile agents by describing recovery curves and the factors affecting the rate of recovery.

g. Describe diffusion hypoxia and explain its significance.

Kindly provided by Dr James Mitchell from his pharmacodynamics series.

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